Process for the production of 1-(aminomethyl) cyclohexane acetic acid

ABSTRACT

A new process is described for the production of 1-(aminomethyl)cyclohexane acetic acid, a pharmaceutical agent used as an anticonvulsant. For this purpose a (1-cyanocyclohexyl)-malonic acid dialkyl ester is decarbalkoxylated to the corresponding (1-cyanocyclohexyl)acetic acid alkyl ester, then transesterified with a benzyl alcohol and finally hydrogenated to form the end product.

This is a divisional of U.S. Ser. No. 612,985, filed on Nov. 15, 1990,now U.S. Pat. No. 5,095,148, patented Mar. 10, 1992.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a new process for the production of1(aminomethyl)cyclohexane acetic acid as well as to(1-cyanocyclohexyl)acetic acid ester as new intermediate products in theprocess according to the invention.

2. Description of Related Art

1-(Aminomethyl)cyclohexane acetic acid is used under the name Gabapentinin medicine as an anticonvulsant. Gabapentin, its use and production aredescribed in Drugs of the Future, Vol. 9, No. 6, 1984, pp. 418 to 419,as well as in U.S. Pat. Nos. 4,024,175 and 4,152,326, which are herebyincorporated by reference in their entireties. Production of Gabapentinunder these known methods is very expensive, however, and includes sevento eight technically difficult and error-prone steps.

SUMMARY OF THE INVENTION

Therefore the object was to find a process that excludes said drawbacks.

This object was able to be obtained with a process for the production of1-(aminomethyl)cyclohexane acetic acid of the formula: ##STR1## Theprocess is characterized in that in a first step a (1-cyanocyclohexyl)malonic acid dialkyl ester of the general formula: ##STR2## in which Ris an alkyl with 1 to 4 carbon atoms, is decarbalkoxylated to thecorresponding (1-cyanocyclohexyl)acetic acid alkyl ester of the generalformula: ##STR3## in which R is defined as above. In a second step, thealkyl ester is transesterified with a benzyl alcohol of the generalformula: ##STR4## i.e., in which R₁ is H, an alkoxy group, a nitro groupor a halogen, in the presence of a basic catalyst to form a(1-cyanocyclohexyl)acetic acid benzyl ester of the general formula:##STR5## in which R₁ is defined as above. Finally the benzyl ester ishydrogenated in the presence of a hydrogenating catalyst to form the endproduct with hydrogen.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The initial products in the process according to the invention are(1-cyanocyclohexyl)malonic acid dialkyl esters of the general formula:##STR6## in which R means an alkyl with 1 to 4 carbon atoms. Thesecompounds are described in Swiss Patent Application CH 3127/88, which ishereby incorporated by reference in its entirety, and are accessible ina simple way from cyclohexanone.

The methyl or ethyl esters preferably are used for the process accordingto the invention.

In the first process step, the initial product is decarbalkoxylated to a(1-cyanocyclohexyl)acetic acid alkyl ester of the general formula:##STR7## in which R means an alkyl with 1 to 4 carbon atoms. Thesecompounds have not been described up to now.

The decarbalkoxylation can be performed according to methods known inthe literature, e.g., according to Krapcho et al., Synthesis 1982, pages805 to 921 and 893 to 914, or according to Aneya et al., TetrahedronLetters 1983, Vol. 24, No. 43 pages 4641 to 4644, which are herebyincorporated by reference in their entirety.

Then suitably the operation is performed in boric anhydride or indipolar aprotic solvents such as dimethyl sulfoxide, in combination withwater as reaction medium at temperatures between 100° and 250° C.Optionally the reaction can be performed in the presence of alkali oralkaline-earth salts, such as alkali or alkaline-earth chlorides,cyanides, or acetates.

The resulting (1-cyanocyclohexyl)acetic acid alkyl ester is suitablyisolated and purified by distillation.

Alternatively, it is also possible to produce the(1-cyanocyclohexyl)acetic acid alkyl esters by alcoholysis of(1-cyanocyclohexyl)acetonitrile of the general formula: ##STR8## with alower aliphatic alcohol in the presence of a mineral acid and thenhydrolyzing the mixture with water.

In this case, the (1-cyanocyclohexyl)acetonitrile is accessibleaccording to New et al., Synthesis 1983, pages 388-389, which is herebyincorporated by reference in its entirety, from the correspondingcyclohexylidene malonic acid ester.

The alcoholysis is performed with a lower alcohol, preferably withmethanol or ethanol, in the presence of a mineral acid from the serieshydrogen chloride, hydrogen bromide or anhydrous sulfuric acid.

Both the alcohol and the mineral acid are suitably used in amounts of 1to 100 equivalents relative to the nitrile.

The reaction temperature is suitably between -20° and 50° C., thepressure between 1 and 10 bars.

Optionally, an additional aprotic solvent, such as, e.g., an aliphaticor aromatic hydrocarbon, an ether, ester, or a halogenated hydrocarboncan be used as reactant together with the alcohol.

The intermediate product (Imidat) occurring in the alcoholysis is notisolated but is directly hydrolyzed with water, preferably in excess, attemperatures between -20° and 100° C. to form the(1-cyanocyclohexyl)acetic acid alkyl ester.

In the subsequent step, the alkyl ester is transesterified with a benzylalcohol of the general formula: ##STR9## in which R₁ means H or analkoxy group, a nitro group or a halogen in the presence of a catalystto form a (1-cyanocyclohexyl)acetic acid benzyl ester of the generalformula: ##STR10## in which R₁ means H or an alkoxy group, a nitro groupor a halogen.

These compounds have not been described up to now.

The transesterification is preferably performed with benzyl alcohol inthe presence of a base as catalyst.

Suitable bases are the cyanides such as, e.g., potassium cyanide,alcoholates such as, e.g., sodium methylate or potassium tert-butylateor tertiary amines such as, e.g., triethylamine orN,N-dimethylaminopyridine.

The catalyst is suitably used in amounts between 0.01 and 10 molpercent, preferably between 0.2 and 3 mol percent.

Advantageously, the operation is performed in the presence of an aproticsolvent, such as dimethyl ether or tetrahydrofuran, or an aromatic oraliphatic hydrocarbon, such as toluene or hexane.

The reaction temperature for the transesterification is suitably between0° C. and the boiling point of the benzyl alcohol used.

The reaction product is suitably isolated and purified by distillation.

Alternatively, the (1-cyanocyclohexyl)acetic acid benzyl ester may alsobe produced by alcoholysis of (1-cyanocyclohexyl)acetonitrile of thegeneral formula: ##STR11## with a benzyl alcohol of the general formula:##STR12## in which R₁ means H or an alkoxy group, a nitro group orhalogen, preferably benzyl alcohol, in the presence of a mineral acid,preferably from the series hydrogen chloride, hydrogen bromide oranhydrous sulfuric acid.

Both the benzyl alcohol and the mineral acid are suitably used inamounts from 1 to 100 equivalents, relative to the nitrile.

The reaction temperature is suitably between -20° and 50° C., thepressure is suitably between 1 and 10 bars.

Optionally an additional aprotic solvent, such as, e.g., an aliphatic oraromatic hydrocarbon, an ether, ester, or a halogenated hydrocarbon canbe used as reactant together with the alcohol.

The intermediate product (Imidat) occurring in the alcoholysis is notisolated but is directly hydrolyzed with water, preferably in excess, attemperatures between -20° and 100° C. to form the(1-cyanocyclohexyl)acetic acid benzyl ester.

In the last step, the catalytic hydrogenation of the benzyl ester withhydrogen to the desired end product, 1(aminomethyl)cyclohexane aceticacid, takes place.

Noble metal catalysts such as platinum, palladium, rhodium, rutheniumcatalysts, optionally applied to inert supports such as activated carbonor aluminum oxide or Raney catalysts such as, e.g., Raney nickel orRaney cobalt catalysts, or (noble) metal oxides, such as, e.g., nickeloxide or platinum oxide can be used as a hydrogenating catalyst.

Suitably, the amount of catalyst varies between 1 and 50 percent byweight, relative to the benzyl ester used.

Advantageously, the benzyl ester is hydrogenated in the presence of asuitable solvent, such as a lower alcohol, e.g., ethanol, methanol; acarboxylic acid, e.g., acetic acid; an ester, e.g., ethyl acetate; or anether or alcohol in combination with ammonia.

The pressure suitably varies in the range of 1 to 100 bars, preferablybetween 2 and 10 bars, the temperature suitably varies between 0° and100° C. The optimal temperature is largely dependent on the catalystused.

The desired product already precipitates in great purity, but optionallycan be further purified by recrystallization.

EXAMPLE 1 Production of (1-cyanocyclohexyl)acetic acid ethyl ester

26.9 g (100 mmol) of (1-cyanocyclohexyl)malonic acid dimethyl ester, 4.3g (100 mmol) or lithium chloride and 3.6 g (200 mmol) of water wereheated in 300 ml of dimethyl sulfoxide for 22 hours to 150° C. Then itwas cooled, mixed with 700 ml of water and extracted with 1000 ml ofpentane. 14.4 g of (1-cyanocyclohexyl)acetic acid ethyl ester wasobtained by distillation of the organic phase, corresponding to a yieldof 74 percent (relative to the (1-cyanocyclohexyl) malonic acid dimethylester used). Data for the product was:

Boiling point: 125°-130° C./2-4 mbars

Elementary analysis for C₁₁ H₁₇ NO₂ (195.3): Cld: C, 67.7%; H, 8.8%; N,7.2%. Fnd: C, 67.7%; H, 8.7%; N, 7.0%.

    ______________________________________                                        .sup.1 H-NMR: (DMSO-D.sub.6, 300 MHz) δ                                 ______________________________________                                        1.20                 (t, 3H)                                                  1.10-1.25            (m, 1H)                                                  1.34-1.56            (m, 4H)                                                  1.61-1.77            (m, 3H)                                                  1.93-2.03            (m, 2H)                                                  2.69                 (s, 2H)                                                  4.11                 (q, 2H)                                                  ______________________________________                                    

EXAMPLE 2 Production of (1-cyanocyclohexyl)acetic acid benzyl ester

401 mg (2 mmol) of (1-cyanocyclohexyl)acetic acid ethyl ester, 1.09 g(10 mmol) of benzyl alcohol and 6 mg (0.1 mmol) of potassium cyanidewere refluxed for 24 hours in 5 ml of toluene. Then the solution waswashed with 25 ml of water, freed of solvent and distilled in highvacuum. 350 mg of (1-cyanocyclohexyl)acetic acid benzyl ester wasobtained, corresponding to a yield of 68 percent (relative to the(1-cyanocyclohexyl)acetic acid ethyl ester used). Data for the productwas:

Boiling point: 148°-152° C./0.1-02 mbar

Elementary analysis for C₁₆ H₁₉ NO₂ (257.3): Cld: C, 74.7%; H, 7.4%; N,5.4%. Fnd: C, 74.9%; H, 7.4%; N, 5.5%.

    ______________________________________                                        .sup.1 H-NMR: (CDCL.sub.3, 300 MHz) δ                                   ______________________________________                                        1.13-1.27            (m, 1H)                                                  1.28-1.42            (m, 2H)                                                  1.59-1.80            (m, 5H)                                                  2.04-2.12            (m, 2H)                                                  2.59                 (s, 2H)                                                  5.12                 (s, 2H)                                                  7.30-7.41            (m, 5H)                                                  ______________________________________                                    

EXAMPLE 3 Production of 1-(aminomethyl)cyclohexane acetic acid

1.0 g (3.8 mmol) of (1-cyanocyclohexyl)acetic acid benzyl ester wasdistilled in 20 ml of methanol, mixed with 0.2 g of Rh/C 5 percent andhydrogenated at 10 bars of hydrogen pressure. After 23 hours at roomtemperature the suspension was filtered, the filtrate was concentratedto 3 ml, mixed with 25 ml of ethanol, concentrated to 4 ml and put onthe cooling shelf. The precipitated product was filtered, washed withethanol and dried. 0.18 g of Gabapentin was obtained, corresponding to ayield of 27 percent (relative to the (1-cyanocyclohexyl)acetic acidbenzyl ester used). Data for the product was:

Melting point: 148°-151° C.

    ______________________________________                                        .sup.1 H-NMR: (CD.sub.3 OD, 300 MHz) δ                                  ______________________________________                                        1.30-1.67            (m, 10H)                                                 2.47                 (s, 2H)                                                  2.89                 (s, 2H)                                                  ______________________________________                                    

EXAMPLE 4 Production of (1-cyanocyclohexyl)acetic acid benzyl ester from(1-cyanocyclohexyl)acetonitrile

1.52 g (10 mmol) of (1cyanocylclohexyl)acetonitrile and 13.1 g (120mmol) of benzyl alcohol were saturated in 20 ml of toluene at 0° C. withHCl gas. After 22 hours, it was mixed with 25 ml of water and 100 ml ofdimethyl ester, stirred well for 30 minutes and filtered. The organicphase was separated and concentrated by evaporation. 13 g of product wasobtained, which according to gas chromatography contained 2.22 percentof (1-cyanocyclohexyl)acetic acid benzyl ester, corresponding to a yieldof 11 percent (relative to the (1-cyanocyclohexyl)acetonitrile used).

EXAMPLE 5 Production of (1-cyanocyclohexyl)acetic acid ethyl ester from(1-cyanocyclohexyl)acetonitrile

(1-Cyanocyclohexyl)acetonitrile (7.60 g, 50 mmol) was suspended in 30 mlof ethanol and saturated (3 bars) with HCl gas in the autoclave at 0° C.After 22 hours it was expanded, evacuated (18 mbars) in 30 minutes,mixed with 150 ml of water and stirred for 3 hours at 10° C. Then it wasconcentrated on the rotary evaporator to 168 g and extracted with 50 mlof ethyl acetate. 4.04 g of (1-cyanocyclohexyl)acetic acid ethyl esterwas able to be isolated from the organic phase by distillation,corresponding to a yield of 41 percent (relative to the(1-cyanocyclohexyl)acetonitrile used).

What is claimed is:
 1. (1-Cyanocyclohexyl)acetic acid ester of theformula: ##STR13## wherein R₂ is a benzyl radical of the formula:##STR14## wherein R is H, an alkoxy group, a nitro group or a halogen.2. The ester according to claim 1 wherein R₁ is H.
 3. The esteraccording to claim 1 wherein R₁ is an alkoxy group.
 4. The esteraccording to claim 1 wherein R₁ is a nitro group.
 5. The ester accordingto claim 1 wherein R₁ is a halogen.